Skin is the largest organ of the human body, weighing approximately 10 pounds and covering an area of about 16 square feet. Skin is responsible for protecting the internal organs from the external world. Skin protects the body from heat, cold and physical injuries. It also provides sensory information about the nature of the external world and is the first defense against invasion by bacteria, viruses and other noxious compounds. The skin is also an excretory organ, disposing of wastes from the body in order to maintain homeostasis.
The epidermis is a stratified squamous epithelium forming the barrier that excludes harmful microbes and retains body fluids. To perform these functions, proliferative basal cells in the innermost layer periodically detach from an underlying basement membrane of extracellular matrix, move outward and eventually die. Once suprabasal, cells stop dividing and enter a differentiation program to form the barrier. The mechanism of stratification is poorly understood. Although studies in vitro have led to the view that stratification occurs through the delamination and subsequent movement of epidermal cells, most culture conditions favor keratinocytes that lack the polarity and cuboidal morphology of basal keratinocytes in tissue. These features could be important in considering an alternative mechanism that stratification occurs through asymmetric cell divisions in which the mitotic spindle orients perpendicularly to the basement membrane.
The primary function of normal intact skin is to control microbial populations that reside on the skin surface and to prevent underlying tissue from becoming invaded by pathogens (Bowler, P. G., et al., “Wound Microbiology and Associated Approaches to Wound Management,” Clinical Microbiology Reviews, 244-269, April 2001, which is herein expressly incorporated by reference in its entirety). Since wound colonization is often microbial involving pathogenic microorganisms, a wound left untreated can become infected. Wounds can be categorized as either acute or chronic. Acute wounds are caused by external damage to intact skin and include surgical wounds, bites, minor cuts and abrasions, and more severe traumatic wounds such as lacerations and gun shot wounds. Chronic wounds are generally caused by endogenous mechanisms due to a predisposition that compromises the integrity of the dermal and epidermal tissue.
Oxygen's Role in Wound Healing
Reports from Jacques Cousteau's divers that they healed wounds significantly better when they lived in an undersea habitat about 35 feet under the surface of the Red Sea stimulated interest in the role of oxygen in wound healing (Hunt, T. K., et al., “Oxygen: at the foundation of wound healing-introduction,” World Journal of Surgery, 28:291-293, 2004 which is herein expressly incorporated by reference in its entirety). Further research led to the consensus that limited supply of oxygen to the wound site represents a key factor for healing. Recent research substantiates that, in biological tissues, oxygen generates reactive derivatives commonly referred to as Reactive Oxygen Species (ROS).
Disrupted vasculature limits the supply of oxygen to the wound-site. Compromised tissue oxygenation or wound hypoxia is viewed as a major factor that limits the healing process as well as wound disinfection. However, oxygen also fuels tissue regeneration, as well as the oxygen-dependent respiratory burst, which is a primary mechanism to resist infection.
Wound healing commences with blood coagulation followed by infiltration of neutrophils and macrophages at the wound site to destroy pathogenic organisms through the release of ROS by an oxygen-consuming respiratory burst. The wound-site has two clear sources of ROS: (i) transient delivery of larger amounts by respiratory burst of phagocytic cells; and (ii) sustained delivery of lower amounts by enzymes present in cells such as the fibroblasts, keratinocytes and endothelial cells. At low concentrations, ROS may serve as signaling messengers in the cell and regulate numerous signal transduction and gene expression processes. Inducible ROS generated in some non-phagocytic cells are implicated in mitogenic signaling.
Diabetes Mellitus
Diabetes mellitus is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. Diabetes can be associated with serious complications and premature death, but people with diabetes can take steps to control the disease and lower the risk of complications.
There are three main types of diabetes: Type I, Type II and Gestational diabetes. Type I diabetes was previously called insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes. Type I diabetes develops when the body's immune system destroys pancreatic beta cells, the only cells in the body that make the hormone insulin that regulates blood glucose. This form of diabetes usually strikes children and young adults, although disease onset can occur at any age. Type I diabetes may account for 5 percent to 10 percent of all diagnosed cases of diabetes. Risk factors for type I diabetes may include autoimmune, genetic and environmental factors.
Type II diabetes was previously called non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes. Type II diabetes may account for about 90 percent to 95 percent of all diagnosed cases of diabetes. It usually begins as insulin resistance, a disorder in which the cells do not use insulin properly. As the need for insulin rises, the pancreas gradually loses its ability to produce insulin. Type II diabetes is associated with older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical inactivity, and race/ethnicity. African Americans, Hispanic/Latino Americans, American Indians, and some Asian Americans and Native Hawaiians or other Pacific Islanders are at particularly high risk for type II diabetes. Type II diabetes is increasingly being diagnosed in children and adolescents.
Gestational diabetes is a form of glucose intolerance that is diagnosed in some women during pregnancy. Gestational diabetes occurs more frequently among African Americans, Hispanic/Latino Americans and American Indians. It is also more common among obese women and women with a family history of diabetes. During pregnancy, gestational diabetes requires treatment to normalize maternal blood glucose levels to avoid complications in the infant. After pregnancy, 5 percent to 10 percent of women with gestational diabetes are found to have type II diabetes. Women who have had gestational diabetes have a 20 percent to 50 percent chance of developing diabetes in the next 5 to 10 years.
Other specific types of diabetes result from specific genetic conditions (such as maturity-onset diabetes of youth), surgery, drugs, malnutrition, infections and other illnesses. Such types of diabetes may account for 1 percent to 5 percent of all diagnosed cases of diabetes
Over 20 million people or 7 percent of the US population have diabetes, of which only an estimated 14.2 million have been diagnosed with the disease (American Diabetes Association). To survive, people with type I diabetes must have insulin delivered by injections or a pump. Many people with type II diabetes can control their blood glucose by following a careful diet and exercise program, losing excess weight and taking oral medication. Many people with diabetes also need to take medications to control their cholesterol and blood pressure. Diabetes self-management education is an integral component of medical care. Among adults with diagnosed diabetes, 12 percent take both insulin and oral medications, 19 percent take insulin only, 53 percent take oral medications only and 15 percent do not take either insulin or oral medications.
Diabetes and Wound Healing
About 60 percent to 70 percent of people with diabetes have mild to severe forms of nervous system damage. The results of such damage include impaired sensation or pain in the feet or hands, slowed digestion of food in the stomach, carpal tunnel syndrome and other nerve problems. Severe forms of diabetic wounds are a major contributing cause of lower-extremity amputations.
Diabetes can affect many parts of the body and can lead to serious complications such as blindness, kidney damage and lower-limb amputations. Working together, people with diabetes and their health care providers can reduce the occurrence of these and other diabetes complications by controlling the levels of blood glucose, blood pressure and blood lipids, and by receiving other preventive care practices in a timely manner. Research studies in the United States and abroad have found that improved glycemic control benefits people with either type I or type II diabetes (Collins, N., “Diabetes, Nutrition, and Wound Healing,” Advances in Skin and Wound Care, 291-294, November 2003, which is herein expressly incorporated by reference in its entirety). In general, for every 1 percent reduction in results of glycosylated hemoglobin A1C (A1C) blood tests (e.g., from 8 percent to 7 percent), the risk of developing microvascular diabetic complications (eye, kidney and nerve disease) is reduced by 40 percent. Blood pressure control can reduce cardiovascular disease (heart disease and stroke) by approximately 33 percent to 50 percent and can reduce microvascular disease (eye, kidney and nerve disease) by approximately 33 percent. In general, for every 10 millimeters of mercury (mm Hg) reduction in systolic blood pressure, the risk for any complication related to diabetes is reduced by 12 percent. Improved control of cholesterol or blood lipids (for example, HDL, LDL and triglycerides) can reduce cardiovascular complications by 20 percent to 50 percent.
U.S. Pat. No. 5,047,249, which is expressly incorporated herein by reference in its entirety, describes compositions and methods for treating skin conditions and promoting wound healing. U.S. Pat. No. 5,487,899, which is expressly incorporated herein by reference in its entirety, describes wound healing compositions. U.S. Pat. No. 6,579,543, which is expressly incorporated herein by reference in its entirety, describes compositions for topical application to the skin.